This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin resistance (IR) is a well-known component of disorders such as Type 2 diabetes and cardiovascular disease. However, short-term IR is also a physiological phenomenon, best exemplified by states such as pregnancy, where IR by the 3rd trimester is severe. Maintenance of normal glucose levels when there is resistance to insulin action is dependent upon the ability of the insulin-secreting beta cells to increase their output in order to overcome this resistance by secreting enough insulin. This proposal will study the physiology of the compensatory increase in insulin secretion in IR. The signal to the beta cell that results in an increase of insulin secretion during IR is not well defined. Though traditionally thought to be glucose, there is reason to suspect that glucose is only part of the signal, if at all. The possibility of alternative signaling, which we have called beta cell compensatory factors (BCCF) for this proposal, will be studied primarily using an experimental model of short-term, drug-induced IR. In support of this model we will also study several spontaneous models of IR.